The Role of AMPK in Inflammation

Without a good definition of an anti-inflammatory diet, the result is continuing dietary confusion. Therefore, a necessary first step is to define inflammation. A good starting point would be to understand that inflammation is caused by an over-activation of the gene transcription factor, Nuclear Factor kappa B (NF-κB). NF-κB is the genetic master switch in every cell in the body that turns on inflammation. Thus, you could correctly state that an anti-inflammatory diet decreases the activity of NF-κB.

You need some inflammation to address microbial invasions or physical injuries, but you also need to turn off that same acute inflammatory response to heal the damage it caused. If that initial inflammation is not turned off, it results in the build-up of chronic low-level inflammation in every organ in your body. The result is increased body fat, early development of chronic diseases (like diabetes and heart disease), and accelerating aging.

NF-κB is inside every cell in the body, and it never enters into the blood. So, how would you test the efficacy of any diet in reducing the over-activation of NF-κB? The first step would be to look for a surrogate blood marker of increased NF-κB activity. The most likely candidate would be cytokines. Cytokines are pro-inflammatory proteins that are produced when NF-κB is activated. These inflammatory proteins enter the blood to activate our immune system.

Until the Covid-19 pandemic, virtually no one had heard of cytokines. Today, we know that all the complications associated with Covid-19 are due to cytokine storms caused by rapidly increasing levels of these inflammatory proteins in the blood. Unfortunately, hundreds of cytokines are known, and more than 30 are elevated once you develop Covid-19 (1).

Furthermore, cytokines are short-lived in the blood and challenging to measure. So, back to the drawing board to define an anti-inflammatory diet.

A less elegant way of measuring NF-κB activity is the measurement of C-reactive protein. C-reactive protein is made in the liver in response to the increasing levels of one cytokine known as IL-6 (2). However, a far better blood marker for a more significant number cytokines in the blood is the AA/EPA ratio (3,4). If the AA/EPA ratio is decreased, then cytokines are reduced. Conversely, if the AA/EPA ratio is high, then cytokines levels are elevated. Thus, using C-reactive protein or the AA/EPA ratio, you have a blood marker of excess NF-κB activity.

Still, you need a link to understand how the diet might reduce excess NF-κB. activity. Without that link, it becomes impossible to define an anti-inflammatory diet. What turns down NF-κB is the master switch of your metabolism known as AMPK (5). Fortunately, AMPK is under robust dietary control (6). Thus, we have a scientific definition of an anti-inflammatory diet: a diet that promotes AMPK activity.

How the diet activates AMPK is complex and explained in greater detail in my most recent book, The Resolution Zone (7). The short answer to activate AMPK, you must restrict calories while increasing your intake of omega-3 fatty acids adds polyphenols (6,7). These dietary concepts are the foundation of the Zone Diet that I developed over 25 years ago (8).

AMPK also never enters the blood. So, how do you know if your diet is activating AMPK? The answer is you use the blood markers that define the Zone. These markers are the TG/HDL ratio, AA/EPA ratio, and glycosylated hemoglobin (HbA1c). The appropriate ranges for each are clearly defined using simple tests that require only a drop of blood (6,7).
AA/EPA ratio: 1.5-3
TG/HDL: <1
HbA1c: 4.9% – 5.1%

If every one of these markers are in their appropriate ranges, you have an excellent indication you are promoting AMPK activity in every cell. The result is much more difficult to develop a cytokine storm.

Every controlled study that has compared the Zone diet to any other diet consisting of an equal number of calories has demonstrated the superiority of the Zone diet to reduce cytokines either measured by C-reactive protein or the AA/EPA ratio (911). Thus, the Zone diet remains the only clinically validated diet that can be accurately described as an anti-inflammatory diet.

An additional benefit of following an anti-inflammatory diet to reduce cytokine levels is that your immune system becomes more robust to attack any type of microbial infection. This benefit is especially critical for managing Covid-19 (12).

However, the greatest benefit of activating AMPK is that it is your pathway to slowing the aging process. All you need to live longer and better is to keep AMPK in a zone using a validated anti-inflammatory diet (6,7).


  1. Guo J et al. Cytokine signature associated with disease severity in COVID-19. Front Immunol. 2021; 12:681516.
  2. Eklund CM. Pro-inflammatory cytokines in CRP baseline regulation. Adv Clin Chem. 2009; 48:111-136.
  3. Endres S et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engle J Med. 1989; 320:265-271.
  4. Tan A et al. Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating pro-inflammatory cytokines in aging adults: A randomized, controlled study. Prostaglandins Leukot Essent Fatty Acids. 2018; 132:23-29.
  5. Salminen A et al. AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan. J Mol Med. 2011; 89:667-676.
  6. Sears B and Saha AK. Dietary control of inflammation and resolution. Front Nutr. 2021; 8:709435.
  7. Sears B. The Resolution Zone. Zone Press. Palm City, FL (2019)
  8. Sears B. The Zone. Regan Books. New York, NY (1995)
  9. Pereira MA et al. Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA. 2004; 292:2482-2490.
  10. Pittas AG et al. The effects of the dietary glycemic load on type 2 diabetes risk factors during weight loss. Obesity. 2006; 14:2200-2209.
  11. Johnston CS et al. Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets. Am J Clin Nutr. 2006; 83:1055-1061.
  12. Iddir M et al. Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: Considerations during the COVID-19 crisis. Nutrients. 2020; 12:1562.
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